Heme oxygenase-1 (HO-1) catalyzes the first step in the degradation of heme. HO-1 cleaves the α-meso carbon bridge of b-type heme molecules by oxidation to yield equimolar quantities of biliverdin IXa, carbon monoxide (CO), and free iron. Subsequently, biliverdin is converted to bilirubin via biliverdin reductase, and the free iron is sequestered into ferritin (the production of which is induced by the free iron).
CO is recognized as an important signaling molecule (Verma et al., Science 259:381-384, 1993). It has been suggested that carbon monoxide acts as a neuronal messenger molecule in the brain (Verma et al.) and as a neuro-endocrine modulator in the hypothalamus (Pozzoli et al., Endocrinology 735:2314-2317, 1994). Like nitric oxide, CO is a smooth muscle relaxant (Utz et al., Biochem Pharmacol. 47:195-201, 1991; Christodoulides et al., Circulation 97:2306-9, 1995) and inhibits platelet aggregation (Mansouri et al., Thromb Haemost. 48:286-8, 1982). Inhalation of low levels of CO has been shown to have anti-inflammatory effects in some models.
Efficient DNA damage repair and checkpoint mechanisms are critical components of normal cellular function to maintain the integrity of genomic DNA (Garinis et al., Nat Cell Biol 10 (11), 1241 (2008); Lombard et al., Cell 120 (4), 497 (2005)). DNA lesions are induced in response to UV or ionizing radiation as well as many chemicals including endogenous metabolites and reactive oxygen species (ROS). DNA repair pathways include repair of damaged bases or single-strand DNA breaks (base excision repair) and repair of double strand DNA breaks (DSB) including homologous recombination (HR) or non-homologous end joining (NHEJ).